4. Airways Function

Question 1

Outline the basic structure and organisation of the airways

Answer 1

Airways are either cartilaginous or alveolar

Their basic function is to either act as conduit pipes or to conduct gas exchange

Their function is facilitated by mechanical stability (cartilage) and control of calibre (smooth muscle)

There are 23 generations of branching from trachea to alveolar sacs, consisting of a conducting, transitional and respiratory zone, where cartilage quantity decreases and smooth muscle increases

Cartilage ring incomplete and slightly offset, but smooth muscle and nervous innervation complete

Question 2

Name and describe the different categories of cells contained within the airways

Answer 2

Lining – ciliated, intermediate, brush and basal

Contractile – smooth muscle

Secretory – goblet (epithelium), mucous, serous (glands)

Connective – fibroblasts, interstitial (elastin, collagen, cartilage)

Neuroendocrine – nerves, ganglia, neuroendocrine, neuroepithelial bodies

Vascular – endothelial, pericyte, plasma

Immune – mast, dendritic, lymphocyte, eosinophil, macrophage, neutrophil

Question 3

Outline the structure of the human airway epithelium

Answer 3

Consists of ciliated epithelial cells with goblet cells protruding through the layer into the lumen of the airway

Mitochondria also prominent

Goblet cells contain mucin granules; these contain mucin in a highly condensed form

Upon secretion, intra-granular mucin expands using ATP absorbing water and swelling

Question 4

Outline the submucosal glands

Answer 4

Acini are functional units of secretory cells present in airways

Mucous cells secrete mucus

Serous cells secret antibacterials e.g. lysozyme

Glands also secrete water and salts e.g. Na+ and Cl-

Question 5

Define ‘acinus’

Answer 5

1) A small sac-like cavity in a gland, surrounded by secretory cells
2) A region of the lung supplied with air from one of the terminal bronchioles

Question 6

Outline human ciliary structure

Answer 6

Apical hook engages with mucus

‘9 + 2’ arrangement allows movement of cilia

~200 per ciliated cell

Cilia beating – engages with mucus when vertical, but otherwise circles back (so as to prevent mucus just being moved back and forth)

Question 7

Outline airway epithelial function

Answer 7

Secretion of mucins, water and electrolyte components of ‘mucus’ (and plasma, mediators etc.)

Movement of mucus by cilia – mucociliary clearance

Physical barrier to foreign substances

Production of regulatory and inflammatory mediators:

o NO (by nitric oxide synthase, NOS)
o CO (by hemeoxygenase, HO)
o Arachidonic acid metabolites, e.g. prostaglandins (COX) o Chemokines, e.g. interleukin (IL)-8
o Cytokines, e.g. GM-CSF
o Proteases

Question 8

Outline the function of airway smooth muscle

Answer 8

Inflammation affects the structure, airway calibre and secretory effects of smooth muscle cells within airways

Structural effects – hypertrophy

Airway calibre (tone) – contractile and relaxation effects

Secretion – mediators, cytokines, chemokines

o Bacterial products stimulate:

• NOS –> NO release
• COX –> prostaglandin release
• Cytokine, chemokine and adhesion molecule release –> inflammatory cell recruitment

Question 9

Outline the trachea-bronchial circulation in terms of airway vasculature

Answer 9

Comprises 1-5% of cardiac output

Blood flow to airway mucosa = 100-150 ml/min/100g tissue (amongst the highest to any tissue)

Bronchial arteries arise from many sites on: aorta, intercostal arteries and others

Blood returns from tracheal circulation via systemic veins

Blood returns from bronchial circulation to both sides of heart via bronchial and pulmonary veins

Question 10

Outline the functions of the airway vasculature

Answer 10

Good gas exchange (airway tissues and blood)

Contributes to the warming of inspired air

Contributes to the humidification of inspired air

Clears inflammatory mediators

Clears inhaled drugs (good/bad, depending on drug)

Supplies airway tissue and lumen with inflammatory cells

Supplies airway tissue and lumen with proteinaceous plasma (‘plasma exudation’); inflammatory mediators (e.g. histamine, platelet activating factor - PAF) transported in the blood to endothelial cells, which stimulates the release of plasma into the layer of epithelial cell

Question 11

Outline the control of airway function

Answer 11

Nerves:

o Parasympathetic – cholinergic
o Sympathetic – adrenergic
o Sensory innervation

Regulatory and inflammatory mediators:

o Histamine
o Arachidonic acid metabolites (e.g. prostaglandins, leukotrienes)
o Cytokines
o Chemokines

Proteinases (e.g. neutrophil elastase)

Reactive gas species (e.g. O2-, NO)

Question 12

Outline the innervation of the airways

Answer 12

Parasympathetic motor pathway (cholinergic) –> constriction via the vagus nerve

Sensory innervation to the brainstem via the nodose ganglion (inferior ganglion of the vagus nerve); also via the dorsal root ganglion to the spinal cord

Sympathetic innervation from the spinal cord via the cervical thoracic ganglion (relaxation); adrenaline from adrenal gland also, leading to relaxation

Question 13

Outline cholinergic mechanisms with regards to the airways

Answer 13

Parasympathetic innervation of submucosal glands, smooth muscle cells (and blood vessels)

Muscarinic receptors involving acetylcholine

Activation leads to mucus secretion, airway smooth muscle contraction (and vasodilation)

Question 14

Outline the regulatory-inflammatory cells in the airways

Answer 14

Cells: eosinophil, neutrophils, macrophages, mast cells, T-lymphocytes

Mediators: histamine, serotonin, adenosine, prostaglandins, leukotrienes, thromboxane, PAF, endothelin, cytokines, chemokines, growth factors, proteinases, reactive gas species

Effects: smooth muscle (both airway and vascular –> constriction and relaxation), secretion (mucus, water etc.), plasma exudation, neural modulation, chemotaxis, remodelling

Note: cells produce more than one mediator, and each mediator has more than one effect

Question 15

Summarise the clinical correlates of respiratory diseases with loss of airway ‘control’

Answer 15

Asthma, COPD, cystic fibrosis

All common conditions

Cause airway inflammation and obstruction

Also leads to airway remodelling

Question 16

Outline asthma

Answer 16

A clinical syndrome characterised by increased airway responsiveness to a variety of stimuli (leading to airway obstruction)

Airflow obstruction varies over short periods of time and is reversible (spontaneously or with drugs)

Dyspnoea, wheezing and cough (varying degrees - mild to severe)

Airway inflammation leads to airway re-modelling; a mucous ‘plug’ forms in the lumen, the basement membrane thickens, epithelial cells become more fragile, etc.

Bronchoconstriction occurs; the airway wall is thrown into fold, and mucous plugs into the lumen

Question 17

Outline COPD

Answer 17

Chronic Obstructive Pulmonary Disease (COPD) is an umbrella term used to describe progressive lung diseases including emphysema, chronic bronchitis, refractory (non-reversible) asthma, and some forms of bronchiectasis

This disease is characterized by increasing breathlessness

Question 18

How are COPD and asthma distinguished from one another

Answer 18

COPD is an umbrella term for progressive lung diseases, and the symptoms are very similar to asthma

Airway obstruction occurs with both diseases; the age of initial presentation is often the distinguishing feature between COPD and asthma; people who have asthma are typically diagnosed as children

They also both have different causes; experts aren’t sure why some people get asthma, while others do not; it is possibly caused by a combination of environmental and inherited (genetic) factors; it is known that exposure to certain kinds of substances (allergens) can trigger allergies

The known cause of COPD in the developed world is smoking; in developing countries, it’s caused by exposure to fumes from burning fuel for cooking and heating

Question 19

Outline neutrophil elastase

Answer 19

Neutrophil elastase is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity

Secreted by neutrophils and macrophages during inflammation, it destroys bacteria and host tissue

It also localises to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases

Neutrophil elastase is an important protease enzyme that when expressed aberrantly can cause emphysema or emphysematous changes; this involves breakdown of the lung structure and increased airspaces; mutations of the ELANE gene cause severe congenital neutropenia, which is a failure of neutrophils to mature

In order to minimise damage to tissues, there are few inhibitors of neutrophil elastase; one group of inhibitors are the Serpins (Serine Protease Inhibitors); neutrophil elastase has been shown to interact with Alpha 2-antiplasmin, which belongs to the Serpin family of proteins

Question 20

Define airway remodelling

Answer 20

Airway remodeling refers to the structural changes that occur in both the large and the small airways of miscellaneous diseases, including asthma